The present invention relates to delta dicarbonyl compounds in which the two Cxe2x95x90O groups are linked by a moiety having three atoms, at least one of which is a heteroatom. The invention further relates to methods for using these compounds in the treatment of cancer and other proliferative diseases, hemoglobinopathies and inherited metabolic disorders and to treat or alleviate various other illnesses and conditions, such as by hematopoietic stimulation. The present invention also relates to methods for using the disclosed compounds in the inhibition of histone deacetylase.
Histones are unique proteins in the nucleus of a cell. DNA is wound around a complex of histones to form nucleosomes. As such, histones are an integral structural element of the chromatin material. The histones complexed with the DNA are susceptible to a range of chemical modifications, one of which is acetylation, and the reverse of which is deacetylation. Acetylation of histone protein is believed to facilitate transcription of the DNA, thereby enhancing gene expression. Histone deacetylase is believed to reverse the process that represses gene expression. Histone dynamics are regulated by two enzymesxe2x80x94histone acetyl transferase and histone deacetylase.
Hyperacetylation due to inhibition of histone deacetylation, and the resulting expression of a latent gene, have been observed or proposed to occur in numerous inherited metabolic diseases and in cancer. The inhibition of histone deacetylase is believed to activate an otherwise dormant fetal gene, which serves as a redundant or back-up gene. Pharmacological inhibition of histone deacetylase, therefore, is believed to induce the expression of represser genes in cancer tissue, inhibit the expression of tumor-promoting genes, and induce the expression of the redundant or back-up gene in patients suffering from various metabolic and hematological diseases. Thus, inhibition of histone deacetylase is proposed to slow the growth of neoplastic cells and/or reverse the deficient process of various metabolic and hematological diseases. Inhibition of histone deacetylase is also believed to play a role in antiprotozoal activity.
Trichostatin is the most potent inhibitor of histone deacetylase observed so far, but due to various drawbacks, such as availability of the material, has not been pursued.
Butyric acid is a natural product that has been known for several decades to be an effective differentiating and antiproliferative agent in a wide spectra of neoplastic cells in vitro. For example, butyric acid has been reported to induce cellular and biochemical changes in cancer cells, to induce apoptosis, and to increase the expression of transfected DNA, although the mechanism of action of butyric acid is unknown. Increased histone acetylation following treatment with butyric acid has been correlated with changes in transcriptional activity and at differentiated states of cells. Butyric acid and its salts, however, have shown low potency in both in vitro assays and clinical trials, and thus require large doses to achieve even minimal therapeutic effects. This can lead to fluid overload and mild alkalosis.
The present invention is directed to dicarbonyl compounds, and methods for using the same, that have also been found to inhibit histone deacetylase. The present compounds show significantly greater activity than butyric acid or its salts. That compounds containing the dicarbonyl moiety of the present invention have the ability to inhibit histone deacetylase has been previously unreported in the art.
The present invention relates to novel dicarbonyl compounds having a unique moiety linking the two carbonyl groups. The linking moiety contains an oxygen, sulfur or nitrogen atom attached to a carbon atom; attached to the opposite end of the carbon atom is either a sulfur, a nitrogen, or another carbon atom. The compounds are useful in the inhibition of histone deacetylase, among other things.
The present invention therefore further relates to methods of treating a patient for an illness, particularly wherein the illness is one in which histone deacetylase inhibition would be beneficial. Examples include cancer, hemoglobinopathies and inherited metabolic disorders. Other illnesses and conditions that can be treated according to the present invention are discussed herein. In the case of histone deacetylase inhibition, the present compounds are believed to function by chelating the zinc ion at the active site of histone deacetylase; the inventor does not wish to be bound by this mechanism, however.
It is therefore an aspect of the invention to provide dicarbonyl compounds having a linking moiety comprising at least one heteroatom.
Another aspect of the invention provides methods for treating a patient sing the present dicarbonyl compounds.
A method for inhibiting histone deacetylase in a patient is also an aspect of the present invention.
These and other aspects of the invention will be apparent upon reviewing the attached specification and appended claims.